ABSTRACT This is a competing renewal of a UM1 application to support the infrastructure of the original Nurses? Health Study (NHS), begun in 1976. The accumulated resources of NHS provide exceptional opportunities for identifying new paradigms in cancer prevention, etiology and survival. The resources encompass: lifestyle, diet and health data from 20 biennial questionnaires spanning 4 decades from 121,700 women; linked residential data on environment and neighborhood; blood samples from 32,826 participants in mid-life; a 2nd blood and morning urine in 18,743 of these women 10 years later; buccal cells from 33,040 women without blood; 62,641 toenail samples; 6,027 pre-diagnostic mammograms; tissue blocks from >14,000 patients across 16 cancers. The scientific contributions of NHS have been equally exceptional. During this funding period, accomplishments include: >400 cancer-related publications; nearly 300 resource-sharing projects by external investigators and pooling projects/consortia (a 130% increase since 2014); and participation in 33 cancer consortia, including 22 NCI consortia. Most importantly, NHS research has meaningfully guided national and international cancer guidelines on issues ranging from diet to adjuvant treatment. Our overarching goals here are to (1) efficiently expand resources with collection of key new data elements and specimens, and (2) maximize the application and sharing of existing resources, facilitating their transformation into novel cancer discoveries. First, NHS women are now >70 years of age. Over 1/3 of cancers in the US occur after age 75, and half of cancer survivors are 70+ years. Many cancer phenotype distributions appear to change with age (e.g., serous ovarian cancer becomes more common). Moreover, in the next 15 years, the proportion of the US population >70 years will grow by 60%. Thus, continued data and tumor tissue collection in NHS is critical to inform new behavioral and biological research on cancer etiology, survival and quality of life in aging. Specifically, in the next funding period, we will continue to: collect questionnaire data on behavior, quality of life, and health in aging; document cancers/ deaths; link with cancer and death registries, and Medicare claims to enhance follow-up; maintain our bio- repository; collect new tissue blocks. Second, we have had great accomplishments in data use/sharing, but this could be further increased to harness the brain-power of more cancer scientists. Mastering the large, complex data systems with decades of accumulated data elements is a challenge that inhibits efficiency of data sharing. In the next funding period, we propose to update and modernize our data systems, to grow support a large community of users via user-friendly tools for data management, visualization, and analysis. This will be done in an exciting collaboration with The Broad Institute, which is leading and developing similar platforms for The Cancer Genome Atlas, the Genotype-Tissue Expression (GTEx) project, and others.